PROJECT SUMMARY/ABSTRACT Developing effective therapies to interfere in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Genome-wide association studies (GWAS) have been instrumental in understanding interindividual variability in the context of disease risk; however, due to the lack of large databases characterizing tumor immune phenotypes, there is a still a gap in our knowledge of the dynamics of tumor-host immune interactions. The Carter laboratory has recently demonstrated the role of genotype at the major histocompatibility complex (MHC) in shaping the landscape of presented somatic mutations (Marty et al. 2017, Marty et al. 2018). MHC genotypes were found to influence oncogenic mutation probabilities; driver mutations effectively presented by an individual?s inherited MHC, and thus subject to immunosurveillance, were less likely to be observed than driver mutations that did not bind the MHC. The common single nucleotide polymorphism (SNP) rs351855 known to be a marker of poor prognosis in several cancers generated a novel binding site for STAT3, suppressing cytotoxic CD8+ and promoting immunosuppressive CD4+FoxP3+CD25+ regulatory T cell infiltration in breast and lung cancer murine models (Kogan et al. 2013). These published findings define a critical role for germline variation in shaping the tumor immune microenvironment that is still poorly explored. For this proposal, we reasoned contrasting ER+ and ER- breast cancer subtypes, which have differences in immune cell infiltration, baseline immunotherapy response rates, and inflammatory effects, could form the basis for novel germline studies. We plan to use the distinct ER+ and ER- breast cancer immune microenvironments to identify and investigate germline variants that modify tumor-immune interactions. Towards this hypothesis, I have identified SNPs significantly associated with immune phenotypes, such as IFN- expression and cytolytic activity, and with cell-type specific effects. Guided by this promising preliminary data, I propose two Specific Aims to 1) elucidate immune associations and regulatory mechanisms of common germline variants differentially associated with ER+ and ER- breast cancer and 2) integrate common and rare germline single nucleotide variants (SNVs) to predict tumor-immune phenotypes. These aims will leverage powerful bioinformatic analyses and develop innovative models to disentangle mechanisms and relevant cell contexts of the variants. Expected outcomes will provide essential insights into the genomic determinants of immune system-mediated tumor elimination and set up future efforts in precision onco-immunology related to cancer risk, progression and treatment responses. The proposed interdisciplinary research will take place at UC San Diego under the guidance of mentors who are experts in cancer genomics, immunology, and clinical medicine. This proposal will help me receive the training to become a successful independent physician-scientist and domain expert in precision onco-immunology.